Significance Due to recent advances in locoregional treatment, distant metastases are emerging as an increasingly important pattern of treatment failure in head and neck squamous cell carcinoma (HNSCC). Using T-HEp3 preclinical model, preliminary data suggests a link between escape from tumor dormancy and metastatic phenotype. These experiments, supplemented by genetic analyses, suggest an important role for both epidermal growth factor receptor (EGFR) activation and cyclooygeanase-2 (COX-2) overexpression in HSNC metastasis. Further, the T-HEp3 model demonstrates urkinase plasminogen activator (uPAR)-driven ligand-independent activation of EGFR resulting in intrinsic resistance to monoclonal antibodies (mAB) that prevent ligand binding to the EGFR receptor. Our long range goal is to understand how to prevent metastases, maintain tumor dormancy and overcome resistance to cetuximab be selectively targeting EGFR and COX-2 using small molecule inhibitors. A more immediate goal is to validate the role of uPAR in inherent resistance to antibody-EGFR mAb therapy. Innovation Our overarching hypothesis proposes that combined EGFR and COX-2 inhibition, in combination with effective locoregional therapy, can effectively prevent distant metastases in HNSCC by inducing and maintaining tumor dormancy. This represents a completely new approach to HNSCC treatment. Specific Aims The specific aims to this hypothesis will: 1) Determine the role of EGFR & COX-2 in escape from dormancy and metastasis development in T-HEp3 HNSCC model; 2) Determine the role of uPAR on resistance to anti-EGFR mAb. Reemphasis of the proposal's innovation: Collectively, these studies will define the critical role of COX-2 and EGFR in the development of distant metastases in HNSCC and highlight a role of uPAR in intrinsic resistance to anti-EGFR mAb. Information from this project will facilitate the clinical development of rational anti-metastasis therapy in HNSCC. Reemphasis of the proposal's innovation Collectively, these studies will define the critical role of COX-2 and EGFR in the development of distant metastases in HNSCC and highlight a role of uPAR in intrinsic resistance to anti-EGFR mAb. Information from this project will facilitate the clinical development of rational antimetastasis therapy in HNSCC. Keywords: head and neck cancer, metastasis, tumor dormancy, EGFR, COX-2